Hypertension and Dyslipidemia Ocular Risks

Key points at a glance

Key Points at a Glance

• Hypertension and dyslipidemia promote systemic arteriosclerosis and are risk factors for systemic vascular diseases reflected in fundus findings.
• Retinal vessels are the only vessels in the body that can be directly observed, serving as a “window” to systemic vascular status for cardiovascular risk assessment ¹⁾.
• Hypertensive retinopathy is graded by the Keith-Wagener-Barker (KWB) classification from grade I to IV, and grade II or higher is associated with a significantly increased risk of cardiovascular events ⁵⁾.
• Hypertension is the most important risk factor for retinal vein occlusion (RVO), with an odds ratio of 3.0 to 5.0 reported ²⁾.
• Approximately 30% of patients with central retinal artery occlusion (CRAO) and about 25% of those with branch retinal artery occlusion (BRAO) have concurrent cerebral infarction within one week of onset.
• If Hollenhorst plaques (cholesterol emboli) are found in the fundus, evaluation for carotid artery disease is necessary, as they are an indicator of stroke risk.
• Medical management of hypertension and dyslipidemia is the top priority for preventing ophthalmic complications, and active collaboration with internal medicine is required.

1. Relationship between Hypertension/Dyslipidemia and Eye Diseases

Hypertension and dyslipidemia promote systemic arteriosclerosis, which is reflected in fundus findings. Retinal vessels are the only vascular bed in the body that can be directly observed macroscopically, and they are considered a “window” reflecting systemic vascular status ¹⁾.

Hypertensive retinopathy is an independent indicator of cardiovascular risk, and changes in retinal arterioles can be used to assess the severity of hypertension and the degree of arteriosclerosis ¹⁾. Hypertension is the most important risk factor for retinal vein occlusion (RVO), with an odds ratio of 3.0 to 5.0 reported ²⁾. Hypertension and dyslipidemia are also major risk factors for retinal artery occlusion (RAO) ³⁾.

In dyslipidemia, in addition to promoting arteriosclerosis, characteristic fundus findings such as Hollenhorst plaques (cholesterol emboli) occur. Xanthelasma and arcus senilis are also important ocular findings of dyslipidemia ⁶⁾.

• The fundus is the only site in the body where blood vessels can be directly observed, serving as a window for cardiovascular risk assessment ¹⁾
• Hypertension is the most important risk factor for retinal vein occlusion, with an OR of 3.0 to 5.0 ²⁾
• Retinal artery occlusion is considered a “retinal stroke” and requires urgent evaluation similar to stroke ³⁾
• Detection of Hollenhorst plaques is an indicator of carotid artery disease and stroke risk
• Ocular findings of dyslipidemia include xanthelasma, arcus corneae, and lipemia retinalis⁶⁾

Q Does high blood pressure affect the eyes?

A

High blood pressure is reflected as vascular changes in the ocular fundus, increasing the risk of retinal vein occlusion, retinal artery occlusion, and ischemic optic neuropathy. Hypertensive fundus changes are evaluated using the Keith-Wagener-Barker (KWB) classification, and grade II or higher is associated with a significantly increased risk of cardiovascular events. The ocular fundus is the only site where systemic vascular status can be directly observed, and fundus examination is useful for cardiovascular risk assessment.

2. Hypertensive fundus changes

Fundus photograph showing hypertensive fundus changes: arteriovenous crossing phenomenon and arteriolar narrowing

Wood F. Hypertensive retinopathy fundus photograph. 2009. Figure 1. Source ID: Wikimedia Commons (File:Hypertensiveretinopathy.jpg). License: CC BY 3.0.

Fundus photograph showing retinal arteriolar narrowing and arteriovenous crossing phenomenon (KWB grade II) due to hypertension. Corresponds to the arteriovenous crossing phenomenon and arteriolar changes discussed in section “2. Hypertensive fundus changes”.

Hypertension causes characteristic changes in the retinal arterioles. There are several classification systems, including the Keith-Wagener-Barker (KWB) classification, which is still used in health checkups.

Keith-Wagener-Barker (KWB) classification:

Grade	Fundus findings
I	Irregularity of arteriolar caliber, mild increase in light reflex
II	Arteriovenous crossing phenomenon (Gunn sign: venous compression and narrowing, Salus sign: venous deflection)
Grade III	Flame-shaped hemorrhages, cotton-wool spots, hard exudates1)
Grade IV	Papilledema (malignant hypertension, hypertensive encephalopathy)1)

In KWB classification, grade II or higher indicates organic changes in retinal arterioles, significantly increasing the risk of stroke and coronary artery disease⁵⁾. Grade IV (malignant hypertension) is an ophthalmic emergency requiring prompt blood pressure control.

Scheie classification:

• Independently evaluates hypertensive changes (H classification) and arteriosclerotic changes (S classification)⁴⁾
• A two-axis classification of H0–H4 / S0–S4, allowing separate assessment of hypertensive and arteriosclerotic changes

Wong-Mitchell simplified classification:

• Three stages: mild, moderate, malignant⁵⁾
• Moderate or higher stages are associated with significantly increased risk of stroke and cardiovascular events⁵⁾
• A large cohort study (ARIC Study) showed that moderate or greater retinal arteriolar narrowing is an independent predictor of coronary artery disease⁵⁾

Arteriovenous ratio (AVR):

• Normal retinal arteriovenous ratio (AVR) is approximately 0.67⁵⁾
• Decreased AVR (narrowing of arteriolar diameter) is a quantitative indicator of hypertension and arteriosclerosis and correlates with cardiovascular risk⁵⁾

Arteriosclerotic fundus changes:

• Copper-wire artery: widening of the light reflex due to hyaline degeneration of the arterial wall
• Silver-wire artery: loss of the blood column reflex due to fibrous thickening of the arterial wall (indicating severe arteriosclerosis)
• Hollenhorst plaque: cholesterol emboli dislodged from atheroma of the carotid artery or aorta, impacted in a retinal artery branch

3. Dyslipidemia and Ocular Diseases

Fundus photograph of the right eye showing a Hollenhorst plaque (cholesterol embolus) in a retinal artery and superior retinal pallor

Yong MH, Mustapha M, Che Hamzah J, et al. Right eye findings showing pale retina and Hollenhorst plaque. 2023. Figure 1. Source ID: Wikimedia Commons (File:Right_eye_findings,_Pale_Retina_and_Hollenhorst_plaque.png). License: CC BY 4.0.

Superior retinal pallor (a) and a cholesterol embolus (Hollenhorst plaque, arrow) impacted at the superior temporal vascular arcade (b) are observed. This corresponds to the Hollenhorst plaque discussed in section “3. Dyslipidemia and Ocular Diseases.”

Dyslipidemia increases the risk of many ocular diseases by promoting arteriosclerosis and also causes characteristic ocular findings.

Arteriosclerotic fundus changes (lipid-related):

• Hollenhorst plaque: cholesterol emboli dislodged from atheroma of the carotid artery or aorta, impacted in a retinal artery. Upon detection, carotid ultrasound and echocardiography are mandatory, and collaboration with neurology and cardiology is necessary for stroke prevention.
• The presence of cholesterol plaques is often asymptomatic but indicates a risk of cerebral embolism.

Characteristic ocular findings of dyslipidemia:

• Arcus senilis: lipid deposition in the peripheral cornea. Appearance before age 50 is considered a sign of dyslipidemia⁶⁾
• Xanthelasma: lipid deposition (yellow plaque-like lesions) on the eyelid skin. Associated with elevated LDL cholesterol⁶⁾
• Lipemia retinalis: a rare finding where retinal vessels become milky white due to hypertriglyceridemia (TG > 2,000 mg/dL)⁷⁾

Dyslipidemia and retinal vein occlusion:

• Dyslipidemia is an independent risk factor for retinal vein occlusion (RVO)²⁾
• The main mechanism is indirect through atherosclerosis

4. Related eye diseases

Fundus photograph of the left eye with branch retinal vein occlusion (BRVO): fan-shaped intraretinal hemorrhages and exudates due to occlusion of the superior temporal vein

Yong KC, Tan AK, Yeap TG, et al. Branch retinal vein occlusion color fundus photograph. 2012. Figure 1. Source ID: Wikimedia Commons (File:Branch_retinal_vein_occlusion.jpg). License: CC BY 2.0.

Left eye fundus image showing fan-shaped intraretinal hemorrhages and hard exudates in the corresponding area due to occlusion of the superior temporal retinal vein. This corresponds to retinal vein occlusion discussed in section “4. Related eye diseases.”

Hypertension and dyslipidemia are directly associated with several major eye diseases.

Retinal vein occlusion (RVO)

Hypertension is the most important risk factor for CRVO: OR 3.0–5.0²⁾

Pathogenesis of BRVO: Hypertension-induced arterial wall thickening compresses the vein at the arteriovenous crossing, causing occlusion²⁾

Treatment for macular edema: Anti-VEGF therapy (e.g., ranibizumab) is effective¹⁰⁾

Basic management: Medical management of hypertension and dyslipidemia is the most important measure for preventing recurrence

Retinal artery occlusion (RAO)

Retinal stroke: Emergency evaluation similar to stroke is required³⁾

Cerebral infarction complication: Approximately 30% of CRAO patients and 25% of BRAO patients have concurrent cerebral infarction within one week

Essential systemic evaluation: Carotid ultrasound, echocardiography, MRI, electrocardiogram (for atrial fibrillation assessment) ³⁾

Acute treatment: t-PA thrombolytic therapy (within 4.5 hours of onset) is effective but not yet approved by insurance

Non-arteritic Anterior Ischemic Optic Neuropathy (NAION)

Risk factors: Hypertension, diabetes, and dyslipidemia are major risk factors ⁸⁾

Role of nocturnal blood pressure dip: Nocturnal dipping (excessive drop in nighttime blood pressure) contributes to optic nerve blood flow impairment in the pathogenesis ⁸⁾

Management: Consider adjusting the timing of antihypertensive medication (e.g., avoid taking before bedtime)

Hypertensive Choroidopathy

Choroidal ischemia in malignant hypertension: Caused by fibrinoid necrosis of choroidal vessels ⁹⁾

Pregnancy-induced hypertension can also cause similar pathology

Characteristic findings: Elschnig spots (depigmented spots due to RPE damage) and Siegrist streaks (linear pigmentation) ⁹⁾

Urgency: Prompt blood pressure control is necessary, similar to KWB classification grade IV

Q Can fundus examination detect arteriosclerosis?

A

The fundus is the only site in the body where blood vessels can be directly observed. The degree of arteriosclerosis can be assessed by findings such as copper-wire arteries, silver-wire arteries, arteriovenous crossing phenomena (Gunn sign, Salus sign), and arteriovenous ratio (AVR), which serve as indicators of cardiovascular risk. If Hollenhorst plaques (cholesterol emboli) are found in the fundus, it may indicate the presence of carotid atherosclerosis, and internal medicine evaluation is necessary from the perspective of stroke risk.

5. Diagnosis and Management

Management of ocular diseases associated with hypertension and dyslipidemia is based on a combination of ophthalmic treatment and systemic medical management.

Ophthalmic examination:

• Dilated fundus examination (ophthalmoscope, fundus camera): evaluation using KWB classification and Scheie classification
• Fluorescein angiography (FA): assessment of retinal circulation and identification of vascular occlusion sites
• OCT: evaluation of macular edema and inner retinal layer damage
• Fundus photography: documentation and follow-up

Systemic evaluation (in collaboration with internal medicine):

• Blood pressure measurement (office, home, 24-hour ambulatory)
• Lipid profile: total cholesterol (TC), LDL-C, HDL-C, triglycerides (TG), HbA1c
• Carotid ultrasound: mandatory when RAO, amaurosis fugax, or Hollenhorst plaque is found ³⁾
• Electrocardiogram and echocardiography: evaluation of atrial fibrillation and valvular disease (mandatory in CRAO patients) ³⁾

Treatment strategy by ocular disease:

• RVO (with macular edema): anti-VEGF therapy (ranibizumab, aflibercept, etc.) ¹⁰⁾
• Acute CRAO: t-PA thrombolytic therapy (within 4.5 hours of onset) is considered effective but is not covered by insurance, so facility-specific management is required
• NAION: if nocturnal hypotension is suspected, discuss adjustment of antihypertensive medication timing with internal medicine

Medical management:

• Antihypertensives: ARBs (angiotensin II receptor blockers) and ACE inhibitors have vascular protective effects ¹¹⁾
• Statins: Lowering LDL-C suppresses progression of atherosclerosis. Meta-analyses have shown a weak protective effect on AMD risk ¹²⁾
• Target blood pressure: <130/80 mmHg (high-risk cases)

Points for referral from ophthalmology to internal medicine

Actively consider referral and collaboration with internal medicine when the following findings are observed.

Emergency or semi-emergency: CRAO (within 4.5 hours of onset → stroke center), KWB grade IV (malignant hypertension → urgent blood pressure management)

Semi-emergency to routine referral: Detection of Hollenhorst plaque (carotid ultrasound, neurology workup), CRVO, BRAO (cardiovascular risk assessment)

Routine collaboration: Initial visit for hypertensive retinopathy (request evaluation of blood pressure, lipids, blood glucose), abnormal findings on health checkup fundus exam (H2 or higher, KWB grade II or higher)

Q What should be done if an abnormality is pointed out on a health checkup fundus examination?

A

Hypertensive retinopathy is an indicator of cardiovascular risk. Findings of KWB grade II or higher and Scheie grade H2 or higher indicate that arteriosclerotic changes have reached an organic stage. In addition to detailed ophthalmologic examination (dilated fundus exam, OCT), evaluation of blood pressure, lipids, and blood glucose by internal medicine is recommended. If a Hollenhorst plaque (bright yellow plaque) is noted, evaluation for carotid artery disease is particularly important, and the patient should promptly see an internist or neurologist.

6. Pathophysiology and detailed mechanisms of onset

The mechanisms by which hypertension and dyslipidemia damage ocular tissues are broadly divided into three categories: structural changes in the vessel wall, blood flow disturbance, and embolic mechanisms.

Progressive stages of retinal arteriolar changes due to hypertension:

• Phase 1 (vasoconstrictive phase): Arterioles constrict as a functional response to hypertension. Irregularity of caliber and increased light reflex (KWB grade I) occur ¹⁾
• Phase 2 (arteriosclerotic phase): Persistent hypertension causes organic thickening of the vessel wall. At arteriovenous crossings where the arterial and venous walls share a common adventitia, the vein is compressed and narrowed (KWB grade II) ²⁾
• Phase 3 (exudative phase): Flame-shaped hemorrhages, cotton-wool spots, and hard exudates due to increased vascular permeability and rupture (KWB grade III) ¹⁾
• Phase 4 (malignant hypertension phase): Fibrinoid necrosis of choroidal vessels and papilledema (KWB grade IV) ⁹⁾

Mechanism of arteriovenous crossing changes (KWB grade II):

• Retinal arterioles and venules share a common adventitia at crossing sites ²⁾
• Hypertension-induced arterial wall thickening compresses the venule via the common adventitia, causing narrowing (Gunn sign)
• Severe compression can displace the venular course (Salus sign)
• This narrowing at the arteriovenous crossing increases the risk of venous thrombosis, directly leading to BRVO

Mechanism of cholesterol emboli (Hollenhorst plaques):

• Micro-cholesterol crystals dislodge from atherosclerotic plaques in the carotid artery or aortic arch ³⁾
• They travel via the bloodstream into the ophthalmic artery, central retinal artery, and branch arteries, becoming impacted at bifurcations
• Observed in the fundus as shiny yellow-orange plaques
• They often do not completely occlude the artery, but indicate the presence of an embolic source (carotid artery) and signify stroke risk

Dyslipidemia and vascular endothelial injury:

• Oxidized LDL cholesterol damages vascular endothelial cells ¹¹⁾
• Endothelial nitric oxide (NO) production decreases, impairing vasodilation
• Foam cell formation → atheromatous plaque formation → plaque destabilization → embolism is the main mechanism.
• Similar changes in choroidal vessels lead to hypertensive choroidopathy and RPE damage ⁹⁾.

Role of nocturnal hypotension in NAION:

• Blood flow to the optic nerve head depends on ocular perfusion pressure (mean blood pressure − intraocular pressure).
• Excessive nocturnal blood pressure dipping reduces optic nerve head blood flow, leading to optic nerve ischemia ⁸⁾.
• Taking antihypertensive medications before bedtime may excessively lower nighttime blood pressure, which should be noted as a risk factor for NAION.

7. Latest Research and Future Perspectives

Note on Information at the Research Stage

The following content includes topics that are at the research stage or under development. It presents current evidence neutrally and does not guarantee the clinical efficacy of any specific intervention.

AI-based prediction of cardiovascular risk from fundus photographs:

• Estimation of cardiovascular risk factors (age, sex, smoking history, systolic blood pressure, etc.) from fundus photographs using deep learning models has been reported ¹³⁾.
• Google research has shown that major cardiovascular event risk can be predicted from fundus photographs ¹³⁾.
• Application to teleophthalmology, using the fundus as a cardiovascular screening tool, is expected.

Prospective studies on retinal vascular parameters and cardiovascular risk:

• The association between quantitative assessment of AVR (arteriovenous ratio), retinal arteriolar diameter, and venular diameter with cardiovascular events is being studied in large prospective cohorts ⁵⁾.
• The ARIC Study (Atherosclerosis Risk in Communities Study) showed that retinal arteriolar narrowing is an independent predictor of coronary artery disease⁵⁾

Quantitative assessment of retinal microcirculation using OCTA:

• Research is investigating whether quantitative assessment of retinal capillary density and avascular area using optical coherence tomography angiography (OCTA) may be useful for early detection of hypertensive retinal changes
• It has been reported that capillary density in the superficial and deep layers is reduced in hypertensive patients

Statins and retinal protective effects:

• The association between statin use and risk of developing AMD has been examined in meta-analyses, suggesting a weak protective effect¹²⁾
• Prospective studies on the effect of statins on RVO risk are also ongoing
• Basic research has shown direct retinal vascular protective effects (pleiotropic effects) of statins, but clinical significance has not been established

8. References

1. Wong TY, Mitchell P. Hypertensive retinopathy. N Engl J Med. 2004;351(22):2310-2317.

2. Hayreh SS, Zimmerman MB, Podhajsky P. Incidence of various types of retinal vein occlusion and their recurrence and demographic characteristics. Am J Ophthalmol. 1994;117(4):429-441.

3. Mac Grory B, Schrag M, Biousse V, et al. Management of central retinal artery occlusion: a scientific statement from the American Heart Association. Stroke. 2021;52(6):e282-e294.

4. Scheie HG. Evaluation of ophthalmoscopic changes of hypertension and arteriolar sclerosis. AMA Arch Ophthalmol. 1953;49(2):117-138.

5. Wong TY, Klein R, Sharrett AR, et al. Retinal arteriolar narrowing and risk of coronary heart disease in men and women. The Atherosclerosis Risk in Communities Study. JAMA. 2002;287(9):1153-1159.

6. Zech LA Jr, Hoeg JM. Correlating corneal arcus with atherosclerosis in familial hypercholesterolemia. Lipids Health Dis. 2008;7:7.

7. Vinger PF, Sachs BA. Ocular manifestations of hyperlipoproteinemia. Am J Ophthalmol. 1970;70(4):563-573.

8. Hayreh SS. Management of ischemic optic neuropathies. Indian J Ophthalmol. 2011;59(2):123-136. PMID: 21350282. PMCID: PMC3116541. doi:10.4103/0301-4738.77024.

9. Tso MO, Jampol LM. Pathophysiology of hypertensive retinopathy. Ophthalmology. 1982;89(10):1132-1145.

10. Campochiaro PA, Heier JS, Feiner L, Gray S, Saroj N, Rundle AC, et al. Ranibizumab for macular edema following branch retinal vein occlusion: six-month primary end point results of a phase III study. Ophthalmology. 2010;117(6):1102-1112.e1. doi:10.1016/j.ophtha.2010.02.021.

11. O’Brien T, Nguyen TT, Zimmermann MB. Hyperlipidemia and diabetes mellitus. Mayo Clin Proc. 1998;73(10):969-976.

12. Ma L, Wang Y, Du J, et al. The association between statin use and risk of age-related macular degeneration. Sci Rep. 2015;5:18280.

13. Poplin R, Varadarajan AV, Blumer K, et al. Prediction of cardiovascular risk factors from retinal fundus photographs via deep learning. Nat Biomed Eng. 2018;2(3):158-164.